The American Cancer Society estimates that a total of 192,370 new invasive breast cancers and 62,280 new cases of in situ breast cancer are diagnosed annually. Women with operable breast cancer undergo Breast Conserving Surgery (BCS), also called lumpectomy or partial mastectomy. On average between 50 to 75% of patients with breast cancer undergo BCS followed by radiation therapy. Approximately 20-70% of women undergoing BCS have to return for a repeat surgery due to incomplete removal of the cancer at the first BCS. There is a significant unmet need for a rapid and practical tool for intra-operative assessment of breast tumor margins. The broad goal of this BRP is to bring multiple investigators from Duke University and the University of Wisconsin, Madison together to develop and validate a miniature optical spectral imaging strategy for intra- operative imaging of tumor margins in patients undergoing BCS. Achieving this goal requires significant innovation in optical physics and engineering, and will leverage advances in thin film detectors, waveguides, and on-board electronics. The specific aims of the proposed work are: (1) to design, construct and refine a miniature spectral imaging device and software for quantitative optical spectral imaging, (2) to verify the spectral imaging technology performance metrics through rigorous bench testing, (3) to develop and optimize an automated device-tissue interface platform and to minimize sources of systematic and random errors at the device-tissue interface, and (4) to test the miniature spectral imaging device for the detection of margin positivity in approximately 150 patients undergoing BCS. The proposed clinical studies will serve as an important basis for larger scale successor clinical studies. It is theorized that the miniature optical spectral imaging system developed and tested in this BRP grant will result in a practical clinical tool for rapid intra- operative assessment of breast tumor margins, i.e., it will help guide the surgeon to either complete the surgery, if margins are negative, or re-excise additional tissue, if margins are positive at the time of first surgery, thus avoiding an un-necessary re-excision. The implications are significant in that tens of thousands of unnecessary surgeries could be prevented each year. The technology proposed in this research could also be extended to the assessment of tumor margins in patients with other types of cancers, including the brain, prostate and head and neck. This novel technology also has the potential to serve as a low cost solution for global cancer diagnostics.